Novel 2-pyridylimidazole compounds

ABSTRACT

Novel alkylsubstituted 2-pyridylimidazoles, halosubstituted-2-pyridylbenzimidazoles, and 2-pyridylimidazopyridines are disclosed. The compounds have pharmaceutical utility as xanthine oxidase inhibitors and/or as antihypertensive.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 017,877, now abandoned,filed Mar. 5, 1979, which in turn is a continuation-in-part ofapplication Ser. No. 891,622, filed Mar. 30, 1978, now abandoned, whichin turn is a continuation-in-part of application Ser. No. 755,777, filedDec. 30, 1976, now abandoned.

BACKGROUND OF THE INVENTION

This invention is concerned with novel 4-alkyl-2-pyridylimidazoles,benzimidazoles and imidazopyridines having pharmaceutical activity.

2,4(or 5)-Disubstituted imidazoles, excluding 4-alkyl imidazoles, aredisclosed in U.S. Pat. No. 3,691,178. These compounds are shown to havexanthine oxidase inhibiting activity, which indicates usefulness fortreating gout or hyperuricemia. U.S. Pat. No. 3,786,061 and Journal ofMedicinal Chemistry, 18, 895-900 (1975) dislcose4(5)-trifluoromethyl-2-pyridiylimidazoles which are shown to havexanthine oxidase and/or antihypertensive activity. No4-alkyl-2-substituted imidazoles are disclosed.

Certain 2-pyridylbenzimidazoles useful as light screening agents aredisclosed in Chemical Abstracts, 58, 2455-e (1963).

2-(2-Pyridyl)-1H-imidazo[4,5-c]pyridines are disclosed in the Journal ofHeterocyclic Chemistry, 4, 157-159 (1967). No utility is disclosed forthese pyridines.

2-(3-Pyridyl)imidazole is disclosed by Fromherz et al in Helv. Physiol.Acta 6 42-54 (1948) and also Chemical Abstracts 42, 8956i (1948). Noalkylimidazole derivatives are suggested.

Certain novel alkyl-2-pyridylimidazoles, halo-2-pyridylbenzimidazoles,and 2-pyridylimidazopyridines have been discovered which exhibitantihypertensive and/or xanthine oxidase inhibiting activity.

SUMMARY OF THE INVENTION

4-Alkyl-2-pyridylimidazoles, 2-pyridylbenzimidazoles, and2-pyridylimidazopyridines and their use for treating hypertension and/orgout or hyperuricemia.

DESCRIPTION OF PREFERRED EMBODIMENT

An embodiment of this invention is compounds selected from the groupconsisting of:

(a) substituted imidazoles having the formula: ##STR1## wherein R is3-pyridyl or 4-pyridyl and R₁ is C₁ -C₅ alkyl, branched and unbranched,e.g. t-butyl, n-pentyl, isopropyl, and pharmaceutically acceptable saltsthereof;

(b) halobenzimidazoles having the formula: ##STR2## wherein R is3-pyridyl or 4-pyridyl, R₂ is bromo or chloro, and R₃ is hydrogen, bromoor chloro, and pharmaceutically acceptable salts thereof; and

(c) imidazopyridines having the formula: ##STR3## wherein R is 3-pyridylor 4-pyridyl, and pharmaceutically acceptable salts thereof.

The pharmaceutically acceptable salts include metal salts, e.g. Na, K,the alkaline earth metals; quaternary salts and acid addition salts ofthe Formula I-IV compounds. The metal salts can be prepared byconventional treatment of the Formula I-IV compounds with suitable base,e.g. NaOH, KOH, CaO, etc. The quaternary salts can be prepared byconventional treatment of the Formula I-IV compound with an alkyl iodidesuch as methyl iodide, ethyl iodide and the like.

The acid addition salts can be prepared by conventional treatment ofFormula I-IV compounds with a suitable inorganic or organic acid.Suitable inorganic acids are the hydrohalides, e.g. HCl, HI, HBr,sulfuric acid, phosphoric acid, and the like.

Suitable organic acids are exemplified by C₂ -C₂₄ carboxylic acids suchas acetic acid, tetracosanoic acid, oleic acid, 2-ethylhexoic acid,maleic acid, pamoic acid, lactic acid, citric acid, succinic acid, malicacid, trimethylacetic acid, oxalic acid, fumaric acid,cyclohexylcarboxylic acid, lauric acid and the like and non-carboxylicacids such as isenthionic acid.

The compounds of the present invention have antihypertensive activityand/or xanthine oxidase (X.O.) inhibiting activity. Some compounds haveboth activities.

The xanthine oxidase activity of representative compounds was determinedusing an in vitro test--the antihypertensive activity was determined byadministration of said compounds to a spontaneously hypertensive (SH) orrenal hypertensive (RH) rat. Results of such tests are tabulated below.The X.O. inhibition is expressed as % inhibition of the enzyme at apresent compound concentration of 2×10⁻⁵ M.

                  TABLE 1                                                         ______________________________________                                        Antihypertensive (AH) and X.O. Inhibiting Activity                                                   A.H.     % X.O.                                        Compound               Activity Inhibition                                    ______________________________________                                         ##STR4##              yes.sup.1                                                                              4                                              ##STR5##              yes.sup.1                                                                              0                                              ##STR6##              yes.sup.2                                                                              11                                             ##STR7##              no       56                                             ##STR8##              yes.sup.1                                                                              8                                              ##STR9##              yes.sup.1                                                                              5                                              ##STR10##             yes.sup.1                                                                              62                                             ##STR11##             no       23                                            ______________________________________                                         .sup.1 = SH rat                                                               .sup.2 = RH rat                                                          

To demonstrate the unexpected improvement in antihypertensive activityconferred by the alkyl substituent on the pyridylimidazole moiety,comparative results were obtained for alkyl and non-alkylpyridylimidazoles administered intraperitoneally to the spontaneouslyhypertensive rat. The comparative data is in the following table:

                  TABLE 2                                                         ______________________________________                                        COMPARATIVE ANTIHYPERTENSIVE DATA                                             IN THE S H RAT                                                                                       DOS-                                                                          AGE      Δ MAP.sup.1                             Test COMPOUND          (mg/kg)  (mm/Hg)                                                                              Avg.Δ                            ______________________________________                                              ##STR12##        20       -1  -13                                                                              -7                                     B                                                                                   ##STR13##        20       -31 -20                                                                              -25                                    C                                                                                   ##STR14##        20       -22 - 10                                                                             -16                                    ______________________________________                                         .sup.1 mean arterial pressure                                            

The data in Table 2 clearly shows that the antihypertensive activity ofan alkylsubstituted-2-pyridylimidazole is on average, 2-31/2 timesgreater (Test C-Test B) than that of an unsubstituted-2-pyridylimidazole(Test A).

The xanthine oxidase inhibiting activity of the present compoundsindicates that they will be useful for treating gout or hyperuricemia inhuman patients. Administration of the compounds for such treatment maybe oral or parenteral, using appropriate dosage forms, e.g. tablets,capsules, sterile solutes, elixirs, etc. Daily dosage for this utilitymay be varied, ranging from about 30 mg. to about 1.5 gm., andpreferably from about 100 to about 800 mg. The antihypertensive activityexhibited by the present compounds indicates that they will be usefulfor treating hypertension (lowering blood pressure) in human patients.Administration of the compounds may be oral or parenteral, e.g.intravenous, intraperitoneal, intramuscular, etc., using appropriatedosage forms, e.g. tablets, capsules, sterile solutions, emulsions, etc.Daily dosage for the utility may be varied ranging from about 10 mg. toabout 1500 mg., preferably from about 100 mg. to about 1000 mg.

Compounds of Formula I are prepared by the reaction of an appropriatepyridinealdehyde with ammonia and ##STR15## where Rn is C₁ -C₅ alkyl, inthe presence of a suitable oxidizing agent such as a cupric salt e.g.,the acetate. The following equation illustrates this reaction: ##STR16##

Compounds of Formula II, III and IV are prepared by the reaction of anappropriate ortho diamine with nicotinic (pyridyl-3-carboxylic acid) orisonicotinic acid (pyridyl-4-carboxylic acid), either at elevatedtemperature, or at elevated temperature in the presence of an acid, e.g.polyphosphoric acid. The following equations illustrate the generalreactions:

The following examples illustrate preparation of compounds of thepresent invention. All temperatures are in °C. unless otherwisespecified.

EXAMPLE 1 Preparation of 4(5)-methyl-2-(4-pyridyl)imidazole

A solution of α-acetoxyacetone (3.5 g., 0.03 mol), Cu(OAc)₂.H₂ O (12 g.,0.06 mol) and pyridine-4-carboxaldehyde (3.2 g., 0.03 mol) in conc. NH₄OH (75 ml) and MeOH (75 ml.) was heated 3 hr. at reflux. After coolingto room temperature, the precipitated solid was removed by filtrationand resuspended in H₂ O at 80°. H₂ S was bubbled into the suspension for1 hr. After filtration, the filtrate was saturated with Na₂ CO₃ andextracted with CHCl₃. The CHCl₃ extract was dried over Na₂ SO₄ andconcentrated to dryness under reduced pressure. The resulting residuewas chromatographed on alumina, activity grade II, and eluted withCHCl₃. After recrystallization from H₃ CCN, 0.55 g. of4(5)-methyl-2-(4-pyridyl)imidazole was obtained (12%); m.p. 154.5°-156°.

Using substantially the same procedure as Example 1 but substitutingpyridine-3-carboxaldehyde for pyridine-4-carboxaldehyde, a 15% yield of4(5)-methyl-2-(3-pyridyl)imidazole, melting at 166°-167° C., wasobtained.

EXAMPLE 2 Preparation of 5-chloro-2-(4-pyridyl)benzimidazole

To a mixture of isonicotinic acid (4.9 g., 0.04 mol) and4-chloro-o-phenylenediamine (5.8 g., 0.041 mol) was added polyphosphoricacid (20 ml.). The mixture was heated to 200° and maintained at thistemperature for 45 min. After cooling, the reaction mixture was pouredonto ice and the solution made basic with conc. NH₄ OH. The resultingyellow solid was removed by filtration, dissolved in isopropanol,filtered and the filtrate concentrated to a solid. Afterrecrystallization from EtOH-H₂ O, 4.5 g. of5-chloro-2-(4-pyridyl)benzimidazole (49.1%) was obtained; m.p. 306-307.

5,6-Dichloro-2-(4-pyridyl)benzimidazole melting at 297° C. was obtained(11.2% yield) using substantially the same procedure as Example 2, butsubstituting 4,5-dichloro-o-phenylene diamine for the4-chloro-o-phenylene diamine.

5-Chloro-2-(3-pyridyl)benzimidazole melting at 244°-246° C. was obtainedin 52.4% yield using substantially the same procedure as in Example 2,but substituting pyridine-3-carboxylic acid for thepyridine-4-carboxylic acid and recrystallizing from H₃ CCN-EtOH insteadof EtOH-H₂ O.

EXAMPLE 3 Preparation of 2-(3-pyridyl)-1H-imidazo[4,5-b]pyridine

A mixture of 2,3-diaminopyridine (5.4 g., 0.05 mol) and nicotinic acid(6.1 g., 0.05 mol) was heated at 240° for 30 min. The resulting darkmelt was allowed to cool and then recrystallized four times from MeOH-H₂O to yield 1.5 g. of 2-(3-pyridyl)-1H-imidazo[4,5-b]pyridine (15.3%);m.p. 284°.

Using substantially the same procedure as in Example 3, the followingreactants produced the imidazopyridines as indicated. All the productswere recrystallized from H₃ CCN-H₂ O.

    ______________________________________                                        Reactants  Product       M.P.       Yield                                     ______________________________________                                        3,4-diamino-                                                                             2-(3-pyridyl)-                                                                              247°-249° C.                                                               20.4%                                     pyridine and                                                                             1H-imidazo[4,5-c]-                                                 pyridine-3-                                                                              pyridine                                                           carboxylic acid                                                               2,3-diamino-                                                                             2-(4-pyridyl)-                                                                              297° C.                                                                           11.2%                                     pyridine and                                                                             1H-imidazo-                                                        pyridine-4-                                                                              [4,5-c]pyridine                                                    carboxylic acid                                                               3,4-diamino-                                                                             2-(4-pyridyl)-                                                     pyridine and                                                                             1H-imidazo-   285°-286° C.                                                               15.3%                                     pyridine-4-                                                                              [4,5-c]pyridine                                                    carboxylic acid.                                                              ______________________________________                                    

Claims to the invention follow.

What is claimed is:
 1. A compound having the formula ##STR18## wherein Ris 4-pyridyl and R₁ is C₁ -C₅ alkyl or pharmaceutically acceptable saltthereof.
 2. Compound of claim 1 wherein said salt is an acid additionsalt.
 3. Compound of claim 1 having the formula ##STR19##
 4. Apharmaceutical composition for treating hypertension containng aneffective amount of a compound selected from the group consistingof2-(4-pyridyl)-5-methylimidazole, and pharmaceutically acceptable saltthereof.
 5. Method of treating hypertension in humans which comprisesadministering an effective amount of compound of claim
 1. 6. The methodof claim 5 wherein said amount is about 10 mg. to about 1500 mg. perday.